Chronic bronchitis is characterized by productive cough and chronic airflow obstruction, with histopathologic tissue changes in the airways including inflammation, bronchoconstriction, mucus hypersecretion, muscle hyperplasia, goblet cell metaplasia, and fibrosis of airways. Inflammation has been recognized to be the pivotal process by which inflammation in chronic bronchitis is initiated and perpetuated remain to be defined. This project focuses upon the role of macrophages and epithelial cells in the onset of the inflammatory process. Central hypotheses to be tested include: 1) airway cells, specifically the airway macrophages leukin-8 (IL-8) with lesser roles played by other neutrophil chemotactic and/or activating cytokines; 2) agents that block production or action of these cytokines will diminish the physiologic and pathologic changes in models of chronic bronchitis. Distinction of whether IL-8 is crucial to the pathogenesis or produced as part of a secondary response is a major goal of this project. To establish the functional significance of IL-8 in the development of chronic airway disease, it should fulfill the following requirements: 1) IL-8 gene expression should correlate temporally and anatomically with the development of disease; 2) IL-8 synthesis and release also should correlate temporally and anatomically with development of disease; and 3) specific neutralization of IL-8 synthesis or function should ameliorate development of disease. Studies will be carried out in rats which develop anatomic and functional changes of chronic bronchitis after exposure to high levels of sulfur dioxide (SO2) as a model of the disease. The relevance of findings in the model will be confirmed in airway macrophages and epithelial cells obtained by bronchial lavage and brushing from human populations of smokers, nonsmokers, and individuals with clinical evidence of chronic airway inflammation.